Hypertrophic Cardiomyopathy 16

Genetic MONDO:0013455 Pathograph 9 Show in embeddings browser Hypertrophic Cardiomyopathy Genetic Disorder

Hypertrophic cardiomyopathy 16 (CMH16) is the MYOZ2-attributed node of the hypertrophic cardiomyopathy gene series. MYOZ2 encodes myozenin-2, also called calsarcin-1, a small sarcomeric Z-disc protein of adult heart and slow-twitch skeletal muscle that tethers the phosphatase calcineurin to alpha-actinin and restrains calcineurin signalling. The entity rests on one linkage family and must be read with an explicit validity caveat. In 2007 a heterozygous p.Ser48Pro allele was found to cosegregate with HCM in a family with six affected members (early-onset symptoms, pronounced hypertrophy and arrhythmias), and a second missense allele (p.Ile246Met) was found in one of 516 further HCM probands. Replication failed: no disease-causing MYOZ2 variant was found among 438 European familial HCM patients, and a burden analysis of 632 HCM cases sequenced for MYOZ2 against ExAC found no significant excess of rare MYOZ2 variation. ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel downgraded the MYOZ2-hypertrophic cardiomyopathy relationship from Limited to **Disputed** in October 2022, noting that the mechanism for disease is unknown, and its published reappraisal states that genes with disputed evidence are not appropriate for diagnostic reporting. The mechanistic picture is itself split. Loss of calsarcin-1 in mice disinhibits calcineurin and sensitises the heart to pressure-overload hypertrophy, which originally suggested a calcineurin model for the human alleles. But transgenic mice expressing the two human HCM alleles develop a mild HCM-like phenotype (myocyte hypertrophy, interstitial fibrosis, preserved systolic function, Z-disc disruption) with calcineurin activity unchanged, pointing instead to a structural Z-disc mechanism. Dismech curates CMH16 as a real MONDO entity whose pathophysiology is a disputed hypothesis; management is that of hypertrophic cardiomyopathy generally.

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Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal dominant HP:0000006
The founding allele segregated as an autosomal dominant trait with six affected heterozygotes in one family, and ClinGen records autosomal dominant as the mode of inheritance for the relationship it classified as Disputed. No other MYOZ2 allele has segregation evidence.
Autosomal dominant inheritance
Show evidence (2 references)
CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z SUPPORT Other
"MYOZ2 | HGNC:1330 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed"
ClinGen records autosomal dominant inheritance for the MYOZ2-HCM relationship, in the same row that classifies it as Disputed.
PMID:17347475 SUPPORT Human clinical
"identified a T-->C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N=6)"
Heterozygous cosegregation across six affected members of one family is the basis for dominant transmission.
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Mechanistic Hypotheses

2
Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
myoz2_z_disc_structural_hcm EMERGING
Evidence balance 2 support
A heterozygous MYOZ2 missense allele produces a mutant calsarcin-1 that is still incorporated at the Z-disc but disrupts Z-disc structure, and the damaged Z-disc, a recognised signalling hub, is the stimulus for myocyte hypertrophy and interstitial fibrosis. The model rests on one transgenic mouse study of the two founding alleles; it has not been tested in human tissue or patient-derived cells, and ClinGen regards the human disease mechanism as unknown.
Pathograph links
MYOZ2 Missense Variant in Calsarcin-1 -> Z-Disc Structural Disruption DIRECT Mutant calsarcin-1 localises to the Z-disc and is accompanied by disrupted, misaligned Z-discs.
MYOZ2 Missense Variant in Calsarcin-1 -> Interstitial Myocardial Fibrosis Interstitial fibrosis develops in mice expressing the human alleles. The intermediate steps between the allele and fibroblast activation are not characterised.
Z-Disc Structural Disruption -> Cardiomyocyte Hypertrophy Proposed link: the abnormal Z-disc, rather than calcineurin or gross contractile failure, initiates the hypertrophic response. Inferred by the authors from the co-occurrence of Z-disc damage and hypertrophy with normal systolic function and unchanged calcineurin activity.
Cardiomyocyte Hypertrophy -> Hypertrophic Cardiomyopathy Myocyte hypertrophy with interstitial fibrosis and preserved systolic function together make up the HCM-like phenotype of the allele models.
Interstitial Myocardial Fibrosis -> Hypertrophic Cardiomyopathy Interstitial fibrosis is one component of the HCM-like phenotype of the allele models.
Show evidence (2 references)
PMID:22987565 SUPPORT INDIRECT Model organism
"Z disk abnormalities might provide the stimulus for the induction of cardiac hypertrophy caused by MYOZ2 mutations."
INDIRECT (mouse): the authors' own conclusion from the transgenic allele models, stated as a possibility.
CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z SUPPORT Other
"The mechanism for disease is unknown."
The expert-panel judgement is why this is curated as an emerging hypothesis rather than an established mechanism.
Calcineurin-NFAT disinhibition model of MYOZ2 hypertrophic cardiomyopathy
myoz2_calcineurin_disinhibition_hcm ALTERNATIVE
Evidence balance 1 support 2 refute
The originally proposed model: because calsarcin-1 inhibits calcineurin, loss of its function would release calcineurin-NFAT signalling and drive a hypertrophic programme. Loss-of-function mouse data support the premise, but the human HCM alleles lie outside the calcineurin- and alpha-actinin-binding regions and did not change calcineurin activity when expressed in mouse heart, so the model is retained as an alternative rather than the default.
Pathograph links
MYOZ2 Missense Variant in Calsarcin-1 -> Calcineurin-NFAT Disinhibition The originally proposed link, by analogy with the null allele: loss of calsarcin-1 function would release calcineurin. The HCM alleles themselves did not change calcineurin activity when expressed in mouse heart, so this edge is contested.
Calcineurin-NFAT Disinhibition -> Cardiomyocyte Hypertrophy Calcineurin-NFAT signalling is a hypertrophic pathway, and its release by loss of calsarcin-1 augments stress-induced myocyte growth. Shown for the null allele under pressure overload, not for the human HCM alleles.
Show evidence (3 references)
PMID:15543153 SUPPORT INDIRECT Model organism
"We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1."
INDIRECT (mouse null allele, not the human missense alleles): establishes the premise of the model, that loss of calsarcin-1 disinhibits calcineurin in vivo.
PMID:22987565 REFUTE INDIRECT Model organism
"We substantiated the null effects of MYOZ2 mutations on calcineurin activity, by multiple complementary methods. The results across methodological platforms were concordant, indicating no discernible effect."
INDIRECT (mouse): cited against the model as applied to the human alleles, whose expression in mouse heart left calcineurin activity unchanged across several assay platforms.
PMID:22987565 REFUTE INDIRECT Model organism
"Thus, the cardiac phenotype in HCM caused by MYOZ2 mutations might be independent of calcineurin activity in the heart."
INDIRECT (mouse): the authors' conclusion that the allele-driven phenotype does not depend on calcineurin, contradicting the disinhibition model for these alleles.
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Discussions and Knowledge Gaps

2
Do the MYOZ2 HCM alleles act through calcineurin disinhibition, the gene's well-established loss-of-function biology, or through a calcineurin-independent structural effect on the Z-disc?
CONTROVERSY myoz2_loss_of_function_vs_hcm_allele_mechanism
Attached to
pathophysiology#Calcineurin-NFAT Disinhibition pathophysiology#Z-Disc Structural Disruption
Knockout and overexpression studies establish calsarcin-1 as a calcineurin inhibitor whose loss sensitises the heart to pressure-overload hypertrophy, which is why the calcineurin model was proposed when the human alleles were found. The only study of the alleles themselves found no change in calcineurin activity and instead found Z-disc disruption. That study is limited by sub-heterozygous mutant protein levels and a human-mouse residue difference at position 246, and it did not test the alleles under pressure overload, so it does not exclude a stress-dependent calcineurin effect. Neither model has been tested in human cardiomyocytes.
Show evidence (1 reference)
PMID:22987565 SUPPORT Model organism
"dissociation of the induction of cardiac hypertrophy from the calcineurin–NFATc activity does not exclude potential contribution of the calcineurin–NFATc hypertrophic pathway to the progression of cardiac hypertrophy or the response of cardiac hypertrophy to increased external load"
The allele study's own statement of what it leaves open.
Is MYOZ2 a Mendelian cause of HCM at all, or are the reported alleles rare benign variants or modifiers?
KNOWLEDGE GAP myoz2_hcm_human_genetic_evidence
Attached to
pathophysiology#MYOZ2 Missense Variant in Calsarcin-1
The human evidence is one family with a sub-significant LOD score of 2.03, one sporadic proband allele, panel findings without segregation, and one allele that co-occurred with an MYH7 variant and was benign in isolation. Replication in 438 familial patients was negative and a case-control burden test in 632 cases showed no significant excess. Additional segregating families or a population burden signal would be needed to move the classification off Disputed.
Show evidence (1 reference)
CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z SUPPORT Other
"More evidence is needed to either support or entirely refute the role MYOZ2 plays in this disease."
The expert-panel statement that defines this gap.
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Pathophysiology

5
MYOZ2 Missense Variant in Calsarcin-1
The proposed initiating lesion is a heterozygous missense variant in MYOZ2, encoding calsarcin-1 (myozenin-2), a Z-disc protein that binds calcineurin and alpha-actinin. The founding alleles p.Ser48Pro and p.Ile246Met affect highly conserved residues. Only p.Ser48Pro has segregation evidence, and ClinGen scores the human genetic evidence as Disputed.
Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy Calcineurin-NFAT disinhibition model of MYOZ2 hypertrophic cardiomyopathy
ventricular cardiomyocyte CL:0002131 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with regular ventricular cardiac myocyte (CL:0002131). CL:0002131 is a cell type from the Cell Ontology.
MYOZ2 hgnc:1330 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYOZ2 (hgnc:1330). hgnc:1330 is a gene from the HUGO Gene Nomenclature Committee.
calcineurin binding GO:0030346 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves calcineurin binding, annotated with protein phosphatase 2B binding (GO:0030346). GO:0030346 is a molecular function from the Gene Ontology. alpha-actinin binding GO:0042805 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves alpha-actinin binding, annotated with actinin binding (GO:0042805). GO:0042805 is a molecular function from the Gene Ontology.
Z disc GO:0030018 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Z disc (GO:0030018). GO:0030018 is a cellular component from the Gene Ontology.
myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Z-Disc Structural Disruption Mutant calsarcin-1 localises to the Z-disc and is accompanied by disrupted, misaligned Z-discs. Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
Interstitial Myocardial Fibrosis Interstitial fibrosis develops in mice expressing the human alleles. The intermediate steps between the allele and fibroblast activation are not characterised. Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
Calcineurin-NFAT Disinhibition The originally proposed link, by analogy with the null allele: loss of calsarcin-1 function would release calcineurin. The HCM alleles themselves did not change calcineurin activity when expressed in mouse heart, so this edge is contested. Calcineurin-NFAT disinhibition model of MYOZ2 hypertrophic cardiomyopathy
Show evidence (4 references)
PMID:17347475 SUPPORT Human clinical
"Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM."
The founding claim attributing HCM to MYOZ2 missense alleles.
PMID:11114196 SUPPORT In vitro / ex vivo
"calsarcins, which tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells"
Defines the normal molecular functions of the gene product, calcineurin and alpha-actinin binding at the Z-line, recorded on this node.
CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z REFUTE Other
"the evidence to support the gene-disease association between MYOZ2 and HCM is disputed"
Cited against the strength of this node: the expert panel does not regard MYOZ2 missense variation as an established cause of HCM.
+ 1 more reference
Z-Disc Structural Disruption
In mice expressing the I246M allele on a hemizygous endogenous background, about 14% of Z-discs are abnormal (poorly formed, interrupted, bulging or slipped, with myofibrillar disarray) compared with under 4% in wild-type transgenic controls. Phospho-ERK1/2 is higher than in wild-type transgenic mice, but the authors judge the data inadequate to name ERK activation as the driver of hypertrophy.
Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
ventricular cardiomyocyte CL:0002131 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with regular ventricular cardiac myocyte (CL:0002131). CL:0002131 is a cell type from the Cell Ontology.
sarcomere organization GO:0045214 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal sarcomere organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology.
Z disc GO:0030018 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Z disc (GO:0030018). GO:0030018 is a cellular component from the Gene Ontology.
Animal models
MYOZ2 S48P and I246M transgenic mice on a Myoz2 hemizygous background Mouse recapitulates The model is the only source of evidence for this node.
Downstream
Cardiomyocyte Hypertrophy Proposed link: the abnormal Z-disc, rather than calcineurin or gross contractile failure, initiates the hypertrophic response. Inferred by the authors from the co-occurrence of Z-disc damage and hypertrophy with normal systolic function and unchanged calcineurin activity. Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
Show evidence (1 reference)
PMID:22987565 SUPPORT INDIRECT Model organism
"was 3.6 ± 0.9% in the MYOZ2WT and 14.3 ± 3.2% in MYOZ2I246M groups (P = 0.003)"
INDIRECT (mouse): quantifies the excess of structurally abnormal Z-discs in mutant mouse hearts; not examined in human tissue.
Cardiomyocyte Hypertrophy
Increased cardiomyocyte cross-sectional area with induction of hypertrophy marker genes, under normal loading conditions and with preserved systolic function. The hypertrophy in the allele models is mild.
Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
ventricular cardiomyocyte CL:0002131 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with regular ventricular cardiac myocyte (CL:0002131). CL:0002131 is a cell type from the Cell Ontology.
cardiac muscle hypertrophy GO:0003300 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves cardiac muscle hypertrophy (GO:0003300). GO:0003300 is a biological process from the Gene Ontology.
Downstream
Left Ventricular Hypertrophy Myocyte hypertrophy is expressed at the organ level as increased septal thickness and left ventricular mass.
Hypertrophic Cardiomyopathy Myocyte hypertrophy with interstitial fibrosis and preserved systolic function together make up the HCM-like phenotype of the allele models. Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
Show evidence (2 references)
PMID:22987565 SUPPORT INDIRECT Model organism
"Histological examination showed increased cardiac myocytes CSA in MYOZ2S48P and MYOZ2I246M"
INDIRECT (mouse): histological measurement of myocyte hypertrophy in mice expressing the human alleles.
PMID:22987565 SUPPORT INDIRECT Model organism
"The expression of cardiac hypertrophy, however, was relatively mild."
INDIRECT (mouse): records that the modelled hypertrophy is mild.
Calcineurin-NFAT Disinhibition
Loss of calsarcin-1 releases calcineurin from inhibition, activates a hypertrophic gene programme without overt hypertrophy, and enhances the hypertrophic response to pressure overload; conversely, calsarcin-1 overexpression blunts angiotensin-II-induced hypertrophy. This is the gene's established physiological role. Whether it participates in human CMH16 is doubtful, because mice expressing the HCM alleles show no change in calcineurin activity. The node and its edges are kept, tagged with the alternative hypothesis group and carrying the contradicting evidence, to record that model; it is not wired directly to the clinical phenotypes.
Calcineurin-NFAT disinhibition model of MYOZ2 hypertrophic cardiomyopathy
ventricular cardiomyocyte CL:0002131 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with regular ventricular cardiac myocyte (CL:0002131). CL:0002131 is a cell type from the Cell Ontology.
calcineurin-NFAT signaling GO:0033173 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased calcineurin-NFAT signaling, annotated with calcineurin-NFAT signaling cascade (GO:0033173). GO:0033173 is a biological process from the Gene Ontology.
Animal models
Calsarcin-1 (Myoz2) knockout mouse Mouse recapitulates Recapitulates calcineurin disinhibition, which is the gene's loss-of-function biology rather than a demonstrated feature of CMH16.
Downstream
Cardiomyocyte Hypertrophy Calcineurin-NFAT signalling is a hypertrophic pathway, and its release by loss of calsarcin-1 augments stress-induced myocyte growth. Shown for the null allele under pressure overload, not for the human HCM alleles. Calcineurin-NFAT disinhibition model of MYOZ2 hypertrophic cardiomyopathy
Show evidence (3 references)
PMID:15543153 SUPPORT INDIRECT Model organism
"The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload."
INDIRECT (mouse null allele): calcineurin disinhibition sensitises the heart to pressure-overload hypertrophy without causing spontaneous hypertrophy.
PMID:18025526 SUPPORT INDIRECT Model organism
"The sarcomeric protein CS1 prevents Ang-II-induced cardiomyocyte hypertrophy at least in part via inhibition of calcineurin signaling."
INDIRECT (inverted, overexpression model): raising calsarcin-1 inhibits calcineurin-dependent hypertrophy, the converse of this node.
PMID:22987565 REFUTE INDIRECT Model organism
"the induction of the cardiac phenotype in the mutant transgenic mice was independent of the calcineurin–NFATc pathway"
INDIRECT (mouse): contradicts this node's relevance to the disease alleles specifically; the HCM alleles produced hypertrophy without calcineurin activation.
Interstitial Myocardial Fibrosis
Interstitial collagen deposition, roughly doubling the collagen volume fraction, in mice expressing either human MYOZ2 HCM allele. No human MYOZ2 carrier has had myocardial fibrosis characterised by histology or late-gadolinium-enhancement imaging, so this is recorded as a model-derived mechanism node rather than a clinical phenotype of the entity.
Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hypertrophic Cardiomyopathy Interstitial fibrosis is one component of the HCM-like phenotype of the allele models. Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
Show evidence (1 reference)
PMID:22987565 SUPPORT INDIRECT Model organism
"Mutant MYOZ2 mice showed molecular, cellular, and gross cardiac hypertrophy, preserved systolic function, and interstitial fibrosis."
INDIRECT (mouse): fibrosis is observed in the allele models; there are no human MYOZ2 tissue data.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypertrophic Cardiomyopathy 16 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Left Ventricular Hypertrophy VERY_FREQUENT Cardiac HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17347475 SUPPORT Human clinical
"The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias."
Hypertrophy is the defining phenotype of the founding family.
Hypertrophic Cardiomyopathy VERY_FREQUENT Cardiac HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17347475 SUPPORT Human clinical
"S48P substitution, which cosegregated with inheritance of HCM (N=6)"
All six affected members of the founding family had HCM.
Arrhythmia Cardiac HP:0011675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arrhythmia (HP:0011675). HP:0011675 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17347475 SUPPORT Human clinical
"The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias."
Arrhythmia is named as a feature of the founding family.
🧬

Genetic Associations

1
MYOZ2
Gene: MYOZ2 hgnc:1330 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYOZ2 (hgnc:1330). hgnc:1330 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED
Show evidence (7 references)
CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z SUPPORT Other
"The MYOZ2 gene has been related with HCM in 7 probands across 4 publications."
ClinGen's count of the entire human genetic evidence base for the association.
CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z SUPPORT Other
"One missense variant with experimental evidence to support its pathogenicity was identified in a patient and was shown to segregate with 5 additional family members"
Identifies p.Ser48Pro as the single allele with both segregation and experimental support.
PMID:17347475 SUPPORT Human clinical
"The maximum logarithm of odds score was 2.03 (P=0.005). All affected members shared a common haplotype, implicating MYOZ2 as the causal gene."
The linkage evidence for the founding family, with a maximum LOD of 2.03, below the conventional threshold of 3 for significant linkage.
+ 4 more references
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Medical Actions

4
Negative Inotropic Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: beta-adrenergic antagonist NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses beta-adrenergic antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus. calcium channel blocker NCIT:C333 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses calcium channel blocker (NCIT:C333). NCIT:C333 is a therapeutic agent from the NCI Thesaurus. disopyramide NCIT:C61730 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses disopyramide (NCIT:C61730). NCIT:C61730 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Symptomatic therapy for HCM with a beta-blocker, a non-dihydropyridine calcium channel blocker or disopyramide. Management in this entity is the management of hypertrophic cardiomyopathy; guideline algorithms branch on obstructive physiology and sudden-death risk, not on genotype, and no MYOZ2-directed therapy exists.
Show evidence (1 reference)
PMID:38718139 SUPPORT Other
"provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"
Establishes the AHA/ACC guideline as the source of HCM management recommendations; cited for scope because the cached record is the abstract rather than the recommendation tables.
Cardiac Myosin Inhibition
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: mavacamten CHEBI:756998 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses mavacamten (CHEBI:756998). CHEBI:756998 is a therapeutic agent from Chemical Entities of Biological Interest. aficamten CHEBI:747213 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses aficamten (CHEBI:747213). CHEBI:747213 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Mavacamten and aficamten are allosteric cardiac myosin inhibitors used for symptomatic obstructive HCM. They act on beta-cardiac myosin rather than on anything MYOZ2-specific; the indication is physiological, not genotypic.
Show evidence (1 reference)
PMID:32871100 SUPPORT Human clinical
"We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy."
Establishes mavacamten's indication in obstructive HCM.
Implantable Cardioverter-Defibrillator
Action: implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Platform: Device
Primary-prevention ICD for patients meeting HCM sudden-death risk criteria. A MYOZ2 variant carries no established risk weight.
Show evidence (1 reference)
PMID:38718139 SUPPORT Other
"provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"
ICD placement follows the guideline's clinical and imaging-based HCM sudden-death risk assessment, not genotype.
Genetic Counseling and Family Screening
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Behavioral / lifestyle
The counselling message is that a MYOZ2 variant found on an HCM panel is not a molecular diagnosis and should not be used to include or exclude relatives; first-degree relatives are offered clinical and imaging surveillance on the basis of the phenotype alone.
Show evidence (1 reference)
PMID:39971408 SUPPORT Other
"Genes with disputed evidence are not appropriate for diagnostic reporting for the disease-entity in question, including variants of uncertain significance."
Underpins the counselling message that a disputed-gene variant should not drive family testing decisions.
🔬

Diagnosis

2
Echocardiography
The clinical diagnosis is the diagnosis of HCM: echocardiographic demonstration of an unexplained hypertrophied, non-dilated left ventricle, with maximal wall thickness of 15 mm or more in adults, and a borderline category of 10-14 mm with supporting features.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27600940 SUPPORT Human clinical
"In adults, a maximal LV wall thickness (LVWT) ≥15 mm, or the equivalent relative to the body surface area in children, was considered the determining criterion for HCM"
States the echocardiographic criterion applied in the cohort in which MYOZ2 variants were reported.
Targeted Hypertrophic Cardiomyopathy Gene Panel
Molecular diagnosis in HCM uses a multigene panel or exome. Because MYOZ2 is ClinGen Disputed for HCM, a MYOZ2 variant should not be reported as causative or used for cascade testing, so no molecular test currently establishes CMH16 in a proband. The patient's hypertrophy is investigated and managed as HCM either way, and a negative core-gene result leaves the case genetically unexplained rather than attributed to MYOZ2.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39971408 SUPPORT Other
"Genes with disputed evidence are not appropriate for diagnostic reporting for the disease-entity in question, including variants of uncertain significance."
States the reporting consequence of a Disputed classification.
📊

Prevalence

1
Worldwide
Unknown Not yet documented
No population prevalence exists for MYOZ2-attributed hypertrophic cardiomyopathy. The available anchors are proband yields in HCM referral series: one candidate missense allele in 516 North American probands and none in 438 European familial HCM patients. ClinGen counts seven probands across four publications in total.
Show evidence (2 references)
PMID:17347475 SUPPORT Human clinical
"we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M)"
One additional candidate allele in 516 probands is the founding study's estimate of how rarely MYOZ2 is implicated.
PMID:18591919 SUPPORT Human clinical
"no disease-causing mutations could be identified in this large cohort of HCM patients"
A zero yield in 438 familial HCM patients places MYOZ2 among the rarest attributed causes of HCM, if it is a cause at all.
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Animal Models

2
MYOZ2 S48P and I246M transgenic mice on a Myoz2 hemizygous background
Cardiac-restricted transgenic mice expressing FLAG-tagged human wild-type or HCM-allele MYOZ2, including bigenic mice carrying the I246M transgene on a hemizygous endogenous Myoz2 background to approximate the human heterozygous genotype. The mutant lines develop mild myocyte and organ hypertrophy, interstitial fibrosis, Z-disc disruption and preserved systolic function, with calcineurin activity unchanged. Caveats: transgene protein was under half of total MYOZ2, residue 246 is valine rather than isoleucine in mouse, and only one S48P line expressed.
Species
Mouse
Genotype
Myh6-promoter human MYOZ2 S48P or I246M transgene; Myoz2+/- bigenic I246M line
Publication
PMID:22987565
Pathograph links
Z-Disc Structural Disruption recapitulates fidelity: moderate The model is the only source of evidence for this node.
Limitations: Transgene overexpression on a mouse background with sub-heterozygous mutant protein levels; no human tissue comparison exists.
Show evidence (1 reference)
PMID:22987565 SUPPORT Model organism
"Electron microscopy showed disrupted and mal-aligned Z disks in the mutant mice."
Z-disc disruption is directly observed in the model.
Show evidence (2 references)
PMID:22987565 SUPPORT Model organism
"our data show that the expression of mutant MYOZ2 proteins, responsible for HCM in humans, induces a mild cardiac phenotype that resembles human HCM"
The authors' summary of the model's fidelity to human HCM.
PMID:22987565 SUPPORT Model organism
"The expression level of the mutant MYOZ2 protein was <50% of the total MYOZ2 level in all five independent lines of mutant MYOZ2 mice, which is lower than the expected level in humans with heterozygous MYOZ2 mutations."
Records the main limitation of the model as stated by its authors.
Calsarcin-1 (Myoz2) knockout mouse
Germline null mice lacking calsarcin-1. They have enhanced calcineurin signalling, an excess of slow skeletal muscle fibres, and a hypertrophic gene programme without baseline hypertrophy, and they show an exaggerated hypertrophic response to pressure overload. The model captures the gene's loss-of-function biology, not the human HCM alleles, which do not affect calcineurin activity when expressed in mouse heart.
Species
Mouse
Genotype
Myoz2-/-
Publication
PMID:15543153
Pathograph links
Calcineurin-NFAT Disinhibition recapitulates fidelity: low Recapitulates calcineurin disinhibition, which is the gene's loss-of-function biology rather than a demonstrated feature of CMH16.
Limitations: Null allele with no spontaneous hypertrophy; the human HCM alleles are missense changes that did not alter calcineurin activity in mouse heart.
Show evidence (1 reference)
PMID:15543153 SUPPORT Model organism
"We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1."
Calcineurin disinhibition is directly shown in the knockout.
Show evidence (1 reference)
PMID:15543153 SUPPORT Model organism
"The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload."
Summarises the knockout cardiac phenotype.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 16
creation_date: "2026-10-13T00:00:00Z"
synonyms:
- CMH16
- MYOZ2 hypertrophic cardiomyopathy
- hypertrophic cardiomyopathy caused by mutation in MYOZ2
- hypertrophic cardiomyopathy type 16
- cardiomyopathy familial hypertrophic 16
- cardiomyopathy, familial hypertrophic, 16
- cardiomyopathy, familial hypertrophic, type 16
- cardiomyopathy, hypertrophic, 16
description: >-
  Hypertrophic cardiomyopathy 16 (CMH16) is the MYOZ2-attributed node of the
  hypertrophic cardiomyopathy gene series. MYOZ2 encodes myozenin-2, also called
  calsarcin-1, a small sarcomeric Z-disc protein of adult heart and slow-twitch
  skeletal muscle that tethers the phosphatase calcineurin to alpha-actinin and
  restrains calcineurin signalling.

  The entity rests on one linkage family and must be read with an explicit
  validity caveat. In 2007 a heterozygous p.Ser48Pro allele was found to
  cosegregate with HCM in a family with six affected members (early-onset
  symptoms, pronounced hypertrophy and arrhythmias), and a second missense allele (p.Ile246Met) was found in one
  of 516 further HCM probands. Replication failed: no disease-causing MYOZ2
  variant was found among 438 European familial HCM patients, and a burden
  analysis of 632 HCM cases sequenced for MYOZ2 against ExAC found no
  significant excess of rare MYOZ2 variation. ClinGen's Hereditary Cardiovascular Disease Gene Curation
  Expert Panel downgraded the MYOZ2-hypertrophic cardiomyopathy relationship from
  Limited to **Disputed** in October 2022, noting that the mechanism for disease
  is unknown, and its published reappraisal states that genes with disputed
  evidence are not appropriate for diagnostic reporting.

  The mechanistic picture is itself split. Loss of calsarcin-1 in mice
  disinhibits calcineurin and sensitises the heart to pressure-overload
  hypertrophy, which originally suggested a calcineurin model for the human
  alleles. But transgenic mice expressing the two human HCM alleles develop a
  mild HCM-like phenotype (myocyte hypertrophy, interstitial fibrosis, preserved
  systolic function, Z-disc disruption) with calcineurin activity unchanged,
  pointing instead to a structural Z-disc mechanism. Dismech curates CMH16 as a
  real MONDO entity whose pathophysiology is a disputed hypothesis; management is
  that of hypertrophic cardiomyopathy generally.
category: Genetic
notes: >-
  MONDO:0013455 is a child of familial hypertrophic cardiomyopathy
  (MONDO:0024573) and corresponds to OMIM 613838. The only gene attributed to it
  is MYOZ2 (hgnc:1330, chromosome 4q26), and that attribution is disputed.

  ClinGen gene-disease validity: the only ClinGen record for MYOZ2 in
  hypertrophic cardiomyopathy (CGGV assertion d74395ba, classified Disputed,
  autosomal dominant, 2022-10-27) is curated against the generic hypertrophic
  cardiomyopathy term MONDO:0005045, not against this entry's disease term, so it
  is cited as evidence throughout but is not copied into
  `genetic[].gene_disease_validity`, which is reserved for a classification of
  this entry's own MONDO disease. `relationship_type: DISPUTED` follows the same
  convention as the MYH6 (CMH14) and TCAP (CMH25) entries.

  Variant-level record. p.Ser48Pro (Osio 2007, the linkage family) is the only
  allele with segregation and experimental support. p.Ile246Met (Osio 2007) is a
  single proband allele. p.Lys12Asn and p.Leu163Ser were reported from an Italian
  NGS panel, the former in a patient who also carried an MYBPC3 variant.
  p.Leu169Gly (Guo 2017) co-occurred with MYH7 p.Ala719His in a five-generation
  Chinese pedigree; ten carriers of the MYOZ2 allele alone were clinically
  normal, and ClinGen excluded it as causative. A p.Pro109Arg variant of
  uncertain significance reported in a pediatric Vietnamese cardiomyopathy
  series is not cited because that cohort was predominantly dilated
  cardiomyopathy.

  Sudden cardiac death and genetic anticipation reported in the Guo pedigree are
  not recorded as phenotypes of this entity, because every severely affected
  member also carried the MYH7 allele.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 16
  term:
    id: MONDO:0013455
    label: hypertrophic cardiomyopathy 16
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    The founding allele segregated as an autosomal dominant trait with six
    affected heterozygotes in one family, and ClinGen records autosomal dominant
    as the mode of inheritance for the relationship it classified as Disputed.
    No other MYOZ2 allele has segregation evidence.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z
    reference_title: "MYOZ2 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYOZ2 | HGNC:1330 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed"
    explanation: >-
      ClinGen records autosomal dominant inheritance for the MYOZ2-HCM
      relationship, in the same row that classifies it as Disputed.
  - reference: PMID:17347475
    reference_title: "Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a T-->C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N=6)"
    explanation: >-
      Heterozygous cosegregation across six affected members of one family is
      the basis for dominant transmission.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence exists for MYOZ2-attributed hypertrophic
    cardiomyopathy. The available anchors are proband yields in HCM referral
    series: one candidate missense allele in 516 North American probands and none
    in 438 European familial HCM patients. ClinGen counts seven probands across
    four publications in total.
  evidence:
  - reference: PMID:17347475
    reference_title: "Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M)"
    explanation: >-
      One additional candidate allele in 516 probands is the founding study's
      estimate of how rarely MYOZ2 is implicated.
  - reference: PMID:18591919
    reference_title: "Sequence analysis of myozenin 2 in 438 European patients with familial hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no disease-causing mutations could be identified in this large cohort of HCM patients"
    explanation: >-
      A zero yield in 438 familial HCM patients places MYOZ2 among the rarest
      attributed causes of HCM, if it is a cause at all.
mechanistic_hypotheses:
- hypothesis_group_id: myoz2_z_disc_structural_hcm
  hypothesis_label: Calcineurin-independent Z-disc structural model of MYOZ2 hypertrophic cardiomyopathy
  status: EMERGING
  description: >-
    A heterozygous MYOZ2 missense allele produces a mutant calsarcin-1 that is
    still incorporated at the Z-disc but disrupts Z-disc structure, and the
    damaged Z-disc, a recognised signalling hub, is the stimulus for myocyte
    hypertrophy and interstitial fibrosis. The model rests on one transgenic mouse
    study of the two founding alleles; it has not been tested in human tissue or
    patient-derived cells, and ClinGen regards the human disease mechanism as
    unknown.
  evidence:
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Z disk abnormalities might provide the stimulus for the induction of cardiac hypertrophy caused by MYOZ2 mutations."
    explanation: >-
      INDIRECT (mouse): the authors' own conclusion from the transgenic allele
      models, stated as a possibility.
  - reference: CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z
    reference_title: "MYOZ2 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism for disease is unknown."
    explanation: >-
      The expert-panel judgement is why this is curated as an emerging
      hypothesis rather than an established mechanism.
- hypothesis_group_id: myoz2_calcineurin_disinhibition_hcm
  hypothesis_label: Calcineurin-NFAT disinhibition model of MYOZ2 hypertrophic cardiomyopathy
  status: ALTERNATIVE
  description: >-
    The originally proposed model: because calsarcin-1 inhibits calcineurin,
    loss of its function would release calcineurin-NFAT signalling and drive a
    hypertrophic programme. Loss-of-function mouse data support the premise, but
    the human HCM alleles lie outside the calcineurin- and alpha-actinin-binding
    regions and did not change calcineurin activity when expressed in mouse
    heart, so the model is retained as an alternative rather than the default.
  evidence:
  - reference: PMID:15543153
    reference_title: "Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1."
    explanation: >-
      INDIRECT (mouse null allele, not the human missense alleles): establishes
      the premise of the model, that loss of calsarcin-1 disinhibits
      calcineurin in vivo.
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "We substantiated the null effects of MYOZ2 mutations on calcineurin activity, by multiple complementary methods. The results across methodological platforms were concordant, indicating no discernible effect."
    explanation: >-
      INDIRECT (mouse): cited against the model as applied to the human
      alleles, whose expression in mouse heart left calcineurin activity
      unchanged across several assay platforms.
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Thus, the cardiac phenotype in HCM caused by MYOZ2 mutations might be independent of calcineurin activity in the heart."
    explanation: >-
      INDIRECT (mouse): the authors' conclusion that the allele-driven
      phenotype does not depend on calcineurin, contradicting the disinhibition
      model for these alleles.
pathophysiology:
- name: MYOZ2 Missense Variant in Calsarcin-1
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The proposed initiating lesion is a heterozygous missense variant in MYOZ2,
    encoding calsarcin-1 (myozenin-2), a Z-disc protein that binds calcineurin
    and alpha-actinin. The founding alleles p.Ser48Pro and p.Ile246Met affect
    highly conserved residues. Only p.Ser48Pro has segregation evidence, and
    ClinGen scores the human genetic evidence as Disputed.
  genes:
  - preferred_term: MYOZ2
    term:
      id: hgnc:1330
      label: MYOZ2
  molecular_functions:
  - preferred_term: calcineurin binding
    term:
      id: GO:0030346
      label: protein phosphatase 2B binding
  - preferred_term: alpha-actinin binding
    term:
      id: GO:0042805
      label: actinin binding
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:17347475
    reference_title: "Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM."
    explanation: >-
      The founding claim attributing HCM to MYOZ2 missense alleles.
  - reference: PMID:11114196
    reference_title: "Calsarcins, a novel family of sarcomeric calcineurin-binding proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "calsarcins, which tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells"
    explanation: >-
      Defines the normal molecular functions of the gene product, calcineurin and
      alpha-actinin binding at the Z-line, recorded on this node.
  - reference: CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z
    reference_title: "MYOZ2 / hypertrophic cardiomyopathy (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "the evidence to support the gene-disease association between MYOZ2 and HCM is disputed"
    explanation: >-
      Cited against the strength of this node: the expert panel does not regard
      MYOZ2 missense variation as an established cause of HCM.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, for several more recently reported HCM genes (TNNC1 21, MYOZ222, ACTN223, ANKRD124) there was no significant excess of rare genetic variation in these HCM cases."
    explanation: >-
      A case-control burden test found no significant excess of rare MYOZ2
      variation in HCM cases compared with ExAC reference samples (MYOZ2 was
      sequenced in 632 cases, so the test has limited power for a very rare
      cause). The digits fused to the gene names are citation superscripts in
      the source text.
  downstream:
  - target: Z-Disc Structural Disruption
    causal_link_type: DIRECT
    hypothesis_groups:
    - myoz2_z_disc_structural_hcm
    description: >-
      Mutant calsarcin-1 localises to the Z-disc and is accompanied by disrupted,
      misaligned Z-discs.
    evidence:
    - reference: PMID:22987565
      reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Immunofluorescence staining showed co-localization of WT and mutant MYOZ2 proteins with α-actinin at the Z disks. Electron microscopy showed disrupted and mal-aligned Z disks in the mutant mice."
      explanation: >-
        INDIRECT (mouse): mutant protein reaches the Z-disc and the Z-disc is
        structurally abnormal in mice expressing the human HCM alleles.
  - target: Interstitial Myocardial Fibrosis
    hypothesis_groups:
    - myoz2_z_disc_structural_hcm
    description: >-
      Interstitial fibrosis develops in mice expressing the human alleles. The
      intermediate steps between the allele and fibroblast activation are not
      characterised.
    evidence:
    - reference: PMID:22987565
      reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "interstitial fibrosis, as indicated by the CVF, was increased by approximately two-fold in MYOZ2S48P, MYOZ2I246M"
      explanation: >-
        INDIRECT (mouse): collagen volume fraction roughly doubled in mice
        expressing either human HCM allele.
  - target: Calcineurin-NFAT Disinhibition
    hypothesis_groups:
    - myoz2_calcineurin_disinhibition_hcm
    description: >-
      The originally proposed link, by analogy with the null allele: loss of
      calsarcin-1 function would release calcineurin. The HCM alleles
      themselves did not change calcineurin activity when expressed in mouse
      heart, so this edge is contested.
    evidence:
    - reference: PMID:15543153
      reference_title: "Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1."
      explanation: >-
        INDIRECT (mouse null allele): loss of calsarcin-1 disinhibits
        calcineurin, the premise for supposing the human alleles act this way.
    - reference: PMID:22987565
      reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
      supports: REFUTE
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "We substantiated the null effects of MYOZ2 mutations on calcineurin activity, by multiple complementary methods. The results across methodological platforms were concordant, indicating no discernible effect."
      explanation: >-
        INDIRECT (mouse): the human HCM alleles expressed in mouse heart did
        not change calcineurin activity, contradicting this edge for these
        alleles.
- name: Z-Disc Structural Disruption
  biological_scale: CELLULAR
  description: >-
    In mice expressing the I246M allele on a hemizygous endogenous background,
    about 14% of Z-discs are abnormal (poorly formed, interrupted, bulging or
    slipped, with myofibrillar disarray) compared with under 4% in wild-type
    transgenic controls. Phospho-ERK1/2 is higher than in wild-type transgenic
    mice, but the authors judge the data inadequate to name ERK activation as
    the driver of hypertrophy.
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  biological_processes:
  - preferred_term: sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  evidence:
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "was 3.6 ± 0.9% in the MYOZ2WT and 14.3 ± 3.2% in MYOZ2I246M groups (P = 0.003)"
    explanation: >-
      INDIRECT (mouse): quantifies the excess of structurally abnormal Z-discs
      in mutant mouse hearts; not examined in human tissue.
  downstream:
  - target: Cardiomyocyte Hypertrophy
    hypothesis_groups:
    - myoz2_z_disc_structural_hcm
    description: >-
      Proposed link: the abnormal Z-disc, rather than calcineurin or gross
      contractile failure, initiates the hypertrophic response. Inferred by the
      authors from the co-occurrence of Z-disc damage and hypertrophy with
      normal systolic function and unchanged calcineurin activity.
    evidence:
    - reference: PMID:22987565
      reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "various Z disk abnormalities were present in the mutant MYOZ2 bigenic mice, which might provide the initial impetus for the induction of cardiac hypertrophy, independent of the calcineurin pathway"
      explanation: >-
        INDIRECT: the causal direction is the authors' inference from
        co-occurrence, not an intervention that rescued the Z-disc.
- name: Cardiomyocyte Hypertrophy
  biological_scale: CELLULAR
  description: >-
    Increased cardiomyocyte cross-sectional area with induction of hypertrophy
    marker genes, under normal loading conditions and with preserved systolic
    function. The hypertrophy in the allele models is mild.
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  evidence:
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Histological examination showed increased cardiac myocytes CSA in MYOZ2S48P and MYOZ2I246M"
    explanation: >-
      INDIRECT (mouse): histological measurement of myocyte hypertrophy in mice
      expressing the human alleles.
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The expression of cardiac hypertrophy, however, was relatively mild."
    explanation: "INDIRECT (mouse): records that the modelled hypertrophy is mild."
  downstream:
  - target: Left Ventricular Hypertrophy
    description: >-
      Myocyte hypertrophy is expressed at the organ level as increased septal
      thickness and left ventricular mass.
    evidence:
    - reference: PMID:22987565
      reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The mutant MYOZ2 mice exhibited echocardiographic evidence of left ventricular hypertrophy as indicated by increased interventricular septal thickness and left ventricular mass"
      explanation: >-
        INDIRECT (mouse): organ-level hypertrophy accompanies the cellular
        hypertrophy in the same allele models.
  - target: Hypertrophic Cardiomyopathy
    hypothesis_groups:
    - myoz2_z_disc_structural_hcm
    description: >-
      Myocyte hypertrophy with interstitial fibrosis and preserved systolic
      function together make up the HCM-like phenotype of the allele models.
    evidence:
    - reference: PMID:22987565
      reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "our data show that the expression of mutant MYOZ2 proteins, responsible for HCM in humans, induces a mild cardiac phenotype that resembles human HCM"
      explanation: >-
        INDIRECT: a mouse phenotype that resembles human HCM, not a human
        observation.
- name: Calcineurin-NFAT Disinhibition
  biological_scale: CELLULAR
  description: >-
    Loss of calsarcin-1 releases calcineurin from inhibition, activates a
    hypertrophic gene programme without overt hypertrophy, and enhances the
    hypertrophic response to pressure overload; conversely, calsarcin-1
    overexpression blunts angiotensin-II-induced hypertrophy. This is the
    gene's established physiological role. Whether it participates in human
    CMH16 is doubtful, because mice expressing the HCM alleles show no change in
    calcineurin activity. The node and its edges are kept, tagged with the
    alternative hypothesis group and carrying the contradicting evidence, to
    record that model; it is not wired directly to the clinical phenotypes.
  biological_processes:
  - preferred_term: calcineurin-NFAT signaling
    term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    modifier: INCREASED
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  evidence:
  - reference: PMID:15543153
    reference_title: "Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload."
    explanation: >-
      INDIRECT (mouse null allele): calcineurin disinhibition sensitises the
      heart to pressure-overload hypertrophy without causing spontaneous
      hypertrophy.
  - reference: PMID:18025526
    reference_title: "Calsarcin-1 protects against angiotensin-II induced cardiac hypertrophy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The sarcomeric protein CS1 prevents Ang-II-induced cardiomyocyte hypertrophy at least in part via inhibition of calcineurin signaling."
    explanation: >-
      INDIRECT (inverted, overexpression model): raising calsarcin-1 inhibits
      calcineurin-dependent hypertrophy, the converse of this node.
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "the induction of the cardiac phenotype in the mutant transgenic mice was independent of the calcineurin–NFATc pathway"
    explanation: >-
      INDIRECT (mouse): contradicts this node's relevance to the disease
      alleles specifically; the HCM alleles produced hypertrophy without
      calcineurin activation.
  downstream:
  - target: Cardiomyocyte Hypertrophy
    hypothesis_groups:
    - myoz2_calcineurin_disinhibition_hcm
    description: >-
      Calcineurin-NFAT signalling is a hypertrophic pathway, and its release by
      loss of calsarcin-1 augments stress-induced myocyte growth. Shown for the
      null allele under pressure overload, not for the human HCM alleles.
    evidence:
    - reference: PMID:15543153
      reference_title: "Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload."
      explanation: >-
        INDIRECT (mouse null allele): calcineurin disinhibition enhances the
        hypertrophic response to pressure overload but does not cause
        spontaneous hypertrophy.
    - reference: PMID:18025526
      reference_title: "Calsarcin-1 protects against angiotensin-II induced cardiac hypertrophy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The sarcomeric protein CS1 prevents Ang-II-induced cardiomyocyte hypertrophy at least in part via inhibition of calcineurin signaling."
      explanation: >-
        INDIRECT (inverted, overexpression model): blocking calcineurin via
        calsarcin-1 prevents myocyte hypertrophy, the converse of this edge.
- name: Interstitial Myocardial Fibrosis
  biological_scale: TISSUE
  description: >-
    Interstitial collagen deposition, roughly doubling the collagen volume
    fraction, in mice expressing either human MYOZ2 HCM allele. No human MYOZ2
    carrier has had myocardial fibrosis characterised by histology or
    late-gadolinium-enhancement imaging, so this is recorded as a model-derived
    mechanism node rather than a clinical phenotype of the entity.
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutant MYOZ2 mice showed molecular, cellular, and gross cardiac hypertrophy, preserved systolic function, and interstitial fibrosis."
    explanation: >-
      INDIRECT (mouse): fibrosis is observed in the allele models; there are
      no human MYOZ2 tissue data.
  downstream:
  - target: Hypertrophic Cardiomyopathy
    hypothesis_groups:
    - myoz2_z_disc_structural_hcm
    description: >-
      Interstitial fibrosis is one component of the HCM-like phenotype of the
      allele models.
    evidence:
    - reference: PMID:22987565
      reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Notably these mice exhibit cardiac and myocytes hypertrophy, myofibrillar disarray, Z disk structural abnormalities, interstitial fibrosis, and preserved systolic function."
      explanation: >-
        INDIRECT (mouse): interstitial fibrosis is listed among the features by
        which the allele models resemble human HCM.
phenotypes:
- category: Cardiac
  name: Left Ventricular Hypertrophy
  description: >-
    Unexplained left ventricular wall thickening is the defining feature of the
    HCM series. The founding family showed pronounced cardiac hypertrophy with
    early onset of symptoms. Beyond that family, wall-thickness data exist only
    for single panel-detected carriers, too few to describe a MYOZ2-specific
    severity pattern.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:17347475
    reference_title: "Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias."
    explanation: Hypertrophy is the defining phenotype of the founding family.
- category: Cardiac
  name: Hypertrophic Cardiomyopathy
  description: >-
    The clinical entity: a hypertrophied, non-dilated left ventricle not
    explained by another cardiac or systemic disease. Every reported MYOZ2
    proband was ascertained through this diagnosis; carriers of the p.Leu169Gly
    allele without an accompanying MYH7 variant were clinically normal.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:17347475
    reference_title: "Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "S48P substitution, which cosegregated with inheritance of HCM (N=6)"
    explanation: All six affected members of the founding family had HCM.
- category: Cardiac
  name: Arrhythmia
  description: >-
    Cardiac arrhythmias were part of the phenotype of the founding family. The
    arrhythmia type is not specified in the abstract, and no mechanism linking
    MYOZ2 to arrhythmia has been studied, so this phenotype is not wired to a
    pathophysiology node.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:17347475
    reference_title: "Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias."
    explanation: Arrhythmia is named as a feature of the founding family.
genetic:
- name: MYOZ2
  gene_term:
    preferred_term: MYOZ2
    term:
      id: hgnc:1330
      label: MYOZ2
  relationship_type: DISPUTED
  notes: >-
    MYOZ2 encodes calsarcin-1 (myozenin-2), a Z-disc protein expressed in adult
    heart and slow-twitch skeletal muscle that binds calcineurin and
    alpha-actinin. Its attribution as a cause of hypertrophic cardiomyopathy is
    ClinGen Disputed (downgraded from Limited on 2022-10-27, against the generic
    hypertrophic cardiomyopathy term MONDO:0005045; see the entry notes for why
    that record is not copied into `gene_disease_validity`). The reported alleles
    are heterozygous missense; no loss-of-function or copy-number allele has been
    reported as causal.
  evidence:
  - reference: CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z
    reference_title: "MYOZ2 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The MYOZ2 gene has been related with HCM in 7 probands across 4 publications."
    explanation: >-
      ClinGen's count of the entire human genetic evidence base for the
      association.
  - reference: CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z
    reference_title: "MYOZ2 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One missense variant with experimental evidence to support its pathogenicity was identified in a patient and was shown to segregate with 5 additional family members"
    explanation: >-
      Identifies p.Ser48Pro as the single allele with both segregation and
      experimental support.
  - reference: PMID:17347475
    reference_title: "Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The maximum logarithm of odds score was 2.03 (P=0.005). All affected members shared a common haplotype, implicating MYOZ2 as the causal gene."
    explanation: >-
      The linkage evidence for the founding family, with a maximum LOD of 2.03,
      below the conventional threshold of 3 for significant linkage.
  - reference: PMID:18591919
    reference_title: "Sequence analysis of myozenin 2 in 438 European patients with familial hypertrophic cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Although a large cohort of more than 400 patients with familial HCM was screened, a disease-associated mutation in MYOZ2 was not identified."
    explanation: Failed replication in a large familial HCM cohort.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, for several more recently reported HCM genes (TNNC1 21, MYOZ222, ACTN223, ANKRD124) there was no significant excess of rare genetic variation in these HCM cases."
    explanation: >-
      No significant case excess of rare MYOZ2 variation in 632 HCM cases
      against ExAC reference samples. The digits fused to the gene names are
      citation superscripts.
  - reference: PMID:28296734
    reference_title: "Genetic anticipation in a special form of hypertrophic cardiomyopathy with sudden cardiac death in a family with 74 members across 5 generations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten of these subjects carried only this mutation, and their clinical manifestations and ECG findings were normal, supporting the notion that MYOZ2-L169G had few pathogenic effects in this family."
    explanation: >-
      Narrowly against p.Leu169Gly as a sufficient cause: ten carriers of the
      MYOZ2 allele alone were clinically normal. The authors suggest at most a
      modifying role alongside MYH7.
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "9 disputed (from limited; ANKRD1, CALR3, MYH6, MYLK2, MYOM1, MYOZ2, MYPN, TCAP, VCL)"
    explanation: >-
      The peer-reviewed reappraisal names MYOZ2 among the nine HCM genes
      downgraded from Limited to Disputed.
treatments:
- name: Negative Inotropic Pharmacotherapy
  description: >-
    Symptomatic therapy for HCM with a beta-blocker, a non-dihydropyridine
    calcium channel blocker or disopyramide. Management in this entity is the
    management of hypertrophic cardiomyopathy; guideline algorithms branch on
    obstructive physiology and sudden-death risk, not on genotype, and no
    MYOZ2-directed therapy exists.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: calcium channel blocker
      term:
        id: NCIT:C333
        label: Calcium Channel Blocker
    - preferred_term: disopyramide
      term:
        id: NCIT:C61730
        label: Disopyramide
  evidence:
  - reference: PMID:38718139
    reference_title: "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"
    explanation: >-
      Establishes the AHA/ACC guideline as the source of HCM management
      recommendations; cited for scope because the cached record is the
      abstract rather than the recommendation tables.
- name: Cardiac Myosin Inhibition
  description: >-
    Mavacamten and aficamten are allosteric cardiac myosin inhibitors used for
    symptomatic obstructive HCM. They act on beta-cardiac myosin rather than on
    anything MYOZ2-specific; the indication is physiological, not genotypic.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
      term:
        id: CHEBI:756998
        label: mavacamten
    - preferred_term: aficamten
      term:
        id: CHEBI:747213
        label: aficamten
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy."
    explanation: Establishes mavacamten's indication in obstructive HCM.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Primary-prevention ICD for patients meeting HCM sudden-death risk criteria.
    A MYOZ2 variant carries no established risk weight.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:38718139
    reference_title: "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"
    explanation: >-
      ICD placement follows the guideline's clinical and imaging-based HCM
      sudden-death risk assessment, not genotype.
- name: Genetic Counseling and Family Screening
  description: >-
    The counselling message is that a MYOZ2 variant found on an HCM panel is
    not a molecular diagnosis and should not be used to include or exclude
    relatives; first-degree relatives are offered clinical and imaging
    surveillance on the basis of the phenotype alone.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Genes with disputed evidence are not appropriate for diagnostic reporting for the disease-entity in question, including variants of uncertain significance."
    explanation: >-
      Underpins the counselling message that a disputed-gene variant should not
      drive family testing decisions.
diagnosis:
- name: Echocardiography
  description: >-
    The clinical diagnosis is the diagnosis of HCM: echocardiographic
    demonstration of an unexplained hypertrophied, non-dilated left ventricle,
    with maximal wall thickness of 15 mm or more in adults, and a borderline
    category of 10-14 mm with supporting features.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:27600940
    reference_title: "Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adults, a maximal LV wall thickness (LVWT) ≥15 mm, or the equivalent relative to the body surface area in children, was considered the determining criterion for HCM"
    explanation: >-
      States the echocardiographic criterion applied in the cohort in which
      MYOZ2 variants were reported.
- name: Targeted Hypertrophic Cardiomyopathy Gene Panel
  description: >-
    Molecular diagnosis in HCM uses a multigene panel or exome. Because MYOZ2
    is ClinGen Disputed for HCM, a MYOZ2 variant should not be reported as
    causative or used for cascade testing, so no molecular test currently
    establishes CMH16 in a proband. The patient's hypertrophy is investigated
    and managed as HCM either way, and a negative core-gene result leaves the
    case genetically unexplained rather than attributed to MYOZ2.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Genes with disputed evidence are not appropriate for diagnostic reporting for the disease-entity in question, including variants of uncertain significance."
    explanation: States the reporting consequence of a Disputed classification.
animal_models:
- name: MYOZ2 S48P and I246M transgenic mice on a Myoz2 hemizygous background
  species: Mouse
  genotype: Myh6-promoter human MYOZ2 S48P or I246M transgene; Myoz2+/- bigenic I246M line
  publication: PMID:22987565
  description: >-
    Cardiac-restricted transgenic mice expressing FLAG-tagged human wild-type or
    HCM-allele MYOZ2, including bigenic mice carrying the I246M transgene on a
    hemizygous endogenous Myoz2 background to approximate the human
    heterozygous genotype. The mutant lines develop mild myocyte and organ
    hypertrophy, interstitial fibrosis, Z-disc disruption and preserved
    systolic function, with calcineurin activity unchanged. Caveats: transgene
    protein was under half of total MYOZ2, residue 246 is valine rather than
    isoleucine in mouse, and only one S48P line expressed.
  evidence:
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "our data show that the expression of mutant MYOZ2 proteins, responsible for HCM in humans, induces a mild cardiac phenotype that resembles human HCM"
    explanation: The authors' summary of the model's fidelity to human HCM.
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The expression level of the mutant MYOZ2 protein was <50% of the total MYOZ2 level in all five independent lines of mutant MYOZ2 mice, which is lower than the expected level in humans with heterozygous MYOZ2 mutations."
    explanation: Records the main limitation of the model as stated by its authors.
  modeled_mechanisms:
  - target: Z-Disc Structural Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model is the only source of evidence for this node.
    limitations: >-
      Transgene overexpression on a mouse background with sub-heterozygous
      mutant protein levels; no human tissue comparison exists.
    evidence:
    - reference: PMID:22987565
      reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Electron microscopy showed disrupted and mal-aligned Z disks in the mutant mice."
      explanation: Z-disc disruption is directly observed in the model.
- name: Calsarcin-1 (Myoz2) knockout mouse
  species: Mouse
  genotype: Myoz2-/-
  publication: PMID:15543153
  description: >-
    Germline null mice lacking calsarcin-1. They have enhanced calcineurin
    signalling, an excess of slow skeletal muscle fibres, and a hypertrophic gene
    programme without baseline hypertrophy, and they show an exaggerated
    hypertrophic response to pressure overload. The model captures the gene's
    loss-of-function biology, not the human HCM alleles, which do not affect
    calcineurin activity when expressed in mouse heart.
  evidence:
  - reference: PMID:15543153
    reference_title: "Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload."
    explanation: Summarises the knockout cardiac phenotype.
  modeled_mechanisms:
  - target: Calcineurin-NFAT Disinhibition
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      Recapitulates calcineurin disinhibition, which is the gene's
      loss-of-function biology rather than a demonstrated feature of CMH16.
    limitations: >-
      Null allele with no spontaneous hypertrophy; the human HCM alleles are
      missense changes that did not alter calcineurin activity in mouse heart.
    evidence:
    - reference: PMID:15543153
      reference_title: "Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1."
      explanation: Calcineurin disinhibition is directly shown in the knockout.
discussions:
- discussion_id: myoz2_loss_of_function_vs_hcm_allele_mechanism
  kind: CONTROVERSY
  prompt: >-
    Do the MYOZ2 HCM alleles act through calcineurin disinhibition, the
    gene's well-established loss-of-function biology, or through a
    calcineurin-independent structural effect on the Z-disc?
  attaches_to:
  - pathophysiology#Calcineurin-NFAT Disinhibition
  - pathophysiology#Z-Disc Structural Disruption
  rationale: >-
    Knockout and overexpression studies establish calsarcin-1 as a calcineurin
    inhibitor whose loss sensitises the heart to pressure-overload hypertrophy,
    which is why the calcineurin model was proposed when the human alleles were
    found. The only study of the alleles themselves found no change in
    calcineurin activity and instead found Z-disc disruption. That study is
    limited by sub-heterozygous mutant protein levels and a human-mouse residue
    difference at position 246, and it did not test the alleles under pressure
    overload, so it does not exclude a stress-dependent calcineurin effect.
    Neither model has been tested in human cardiomyocytes.
  evidence:
  - reference: PMID:22987565
    reference_title: "Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "dissociation of the induction of cardiac hypertrophy from the calcineurin–NFATc activity does not exclude potential contribution of the calcineurin–NFATc hypertrophic pathway to the progression of cardiac hypertrophy or the response of cardiac hypertrophy to increased external load"
    explanation: >-
      The allele study's own statement of what it leaves open.
- discussion_id: myoz2_hcm_human_genetic_evidence
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is MYOZ2 a Mendelian cause of HCM at all, or are the reported alleles rare
    benign variants or modifiers?
  attaches_to:
  - pathophysiology#MYOZ2 Missense Variant in Calsarcin-1
  rationale: >-
    The human evidence is one family with a sub-significant LOD score of 2.03,
    one sporadic proband allele, panel findings without segregation, and one
    allele that co-occurred with an MYH7 variant and was benign in isolation.
    Replication in 438 familial patients was negative and a case-control
    burden test in 632 cases showed no significant excess. Additional segregating families or a population burden signal
    would be needed to move the classification off Disputed.
  evidence:
  - reference: CGGV:assertion_d74395ba-66ee-43c6-8d3c-c353bd8e5e82-2022-10-27T160000.000Z
    reference_title: "MYOZ2 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More evidence is needed to either support or entirely refute the role MYOZ2 plays in this disease."
    explanation: The expert-panel statement that defines this gap.
references:
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview."
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:20301725
Nonsyndromic Hypertrophic Cardiomyopathy Overview.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Hypertrophic Cardiomyopathy 16 (MYOZ2) · 2026-10-13T18:20:02Z · View source

New entry for hypertrophic cardiomyopathy 16 (MONDO:0013455), the MYOZ2/calsarcin-1 node of the HCM series, replacing stubs/Hypertrophic_Cardiomyopathy_16.yaml. Deep research: research/Hypertrophic_Cardiomyopathy_16-deep-research-claude_code.md (preflight-dr PASS; 15/15 references resolved; PMID:7618393 flagged off topic and not cited; the report's suggestion to record the ClinGen tier in gene_disease_validity was not followed, see below). relationship_type is DISPUTED following the CMH14 (MYH6) and CMH25 (TCAP) precedent: ClinGen classifies MYOZ2-HCM as Disputed (downgraded from Limited 2022-10-27). That ClinGen record is curated against generic HCM (MONDO:0005045), not MONDO:0013455, so it is cited as evidence and explained in notes but not copied into gene_disease_validity (list-gene-validity reports it as other_disease). Pathophysiology is scoped to two mechanistic hypotheses: an EMERGING calcineurin-independent Z-disc structural model (Ruggiero 2013 allele-transgenic mice) and an ALTERNATIVE calcineurin-disinhibition model (Frey 2004 knockout, Frank 2007 overexpression) that the allele mice contradict; recorded as a CONTROVERSY discussion. Human genetic evidence includes REFUTE items from the negative 438-patient European screen (PMID:18591919), the Walsh 2017 burden analysis (PMID:27532257, MYOZ2 named explicitly in the HCM panel), and the Guo 2017 pedigree where L169G-only carriers were unaffected. Sudden cardiac death and anticipation from the Guo pedigree are deliberately not recorded as phenotypes because all severely affected members also carried MYH7 A719H. Arrhythmia (founding family) is left unwired because no mechanism links MYOZ2 to it. GeneReviews HCM overview (PMID:20301725) tagged in references; no MYOZ2-specific chapter exists. Validated with just validate, validate-terms, count-verified-snippets, check-causal-targets, check-entity-refs, check-duplicate-keys, check-gene-validity, the snippet/title/hyphen/retired-prose gates, check-gene-activity-grounding --against-ref origin/main, and validate-disorders.

Claude Code ▸
Hypertrophic Cardiomyopathy 16 (CMH16; MYOZ2-related HCM): research report
claude-haiku-5-5, claude-opus-5-5 10 citations 2026-10-13T14:05:27.590146

I'm pulling the primary MYOZ2/CMH16 sources (Osio 2007, the Posch 2008 screen, ClinGen) and will then write the report.

Hypertrophic Cardiomyopathy 16 (CMH16; MYOZ2-related HCM): research report

Bottom line for curation. CMH16 is a single-gene subtype of autosomal-dominant hypertrophic cardiomyopathy (HCM) attributed to heterozygous missense variants in MYOZ2. MYOZ2 encodes myozenin-2, also called calsarcin-1. It is a sarcomeric Z-disc protein that binds calcineurin and α-actinin. The human genetic evidence is thin:

  • One linkage family: a family with six affected members, carrying the S48P variant (Osio et al. 2007, PMID:17347475).
  • One sporadic missense: I246M, found by screening 516 probands in the same study.
  • A negative replication: a screen of 438 European familial-HCM patients found no disease-causing MYOZ2 mutations (PMID:18591919).
  • A large burden study that does not support most minor HCM genes (PMID:27532257).

ClinGen moved MYOZ2–HCM from Limited to Disputed on 2022-10-27. A KB entry should state this up front. Most mechanistic content comes from mice and cell culture.

The verbatim quotes below come from the abstracts already cached in this worktree's references_cache/ (7 PMIDs plus the ClinGen record). PMIDs that are not yet cached are marked [not cached]. Run just fetch-reference on those before quoting them.

1. Disease information

What it is. CMH16 is left ventricular hypertrophy (LVH) caused by a MYOZ2 mutation, without another explanation for the hypertrophy. MedGen defines it as "hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the MYOZ2 gene."

Identifier Value Status
MONDO MONDO:0013455 given in the prompt; also listed by DrugMap
OMIM (phenotype) 613838 "Cardiomyopathy, familial hypertrophic, 16" confirmed via LOVD
MedGen 462554 / UMLS C3151204 MedGen search result
Gene MYOZ2, 4q26; HGNC:1330 (written hgnc:1330 in this repo); NCBI Gene 51778 HGNC from the ClinGen record; Gene ID from GenScript
Gene OMIM 605602 from memory — verify
UniProt Q9NPC6 from memory — verify
Orphanet no CMH16-specific ORPHA code found; the parent is familial isolated HCM (ORPHA:217569, from memory — verify)
ICD-10 / ICD-11 parent only: I42.1 / I42.2 (obstructive / other HCM); BC43.1 in ICD-11
Parent MONDO (used by ClinGen) MONDO:0005045 hypertrophic cardiomyopathy ClinGen record

Synonyms: CMH16; familial hypertrophic cardiomyopathy 16; MYOZ2-related HCM; calsarcin-1-related HCM.

Source of the information: aggregated disease-level resources (OMIM, MedGen, ClinGen, LOVD, PanelApp) plus a handful of family and cohort reports. There are no EHR or registry data specific to MYOZ2.

2. Etiology

Cause. Heterozygous germline missense variants in MYOZ2 (autosomal dominant). - Osio et al. 2007 (Circ Res, PMID:17347475 [not cached]): genome-wide linkage in a family with six affected members, after four known sarcomere genes had been excluded, mapped HCM to 4q26–q27. Sequencing MYOZ2 there found p.Ser48Pro (S48P), which segregated with disease and was absent from several hundred control chromosomes. Screening 516 HCM probands found a second missense, p.Ile246Met (I246M). The authors concluded: "We conclude MYOZ2 is a novel causal gene for human HCM."

Contrary and diluting evidence. - Posch et al. 2008 (Med Sci Monit, PMID:18591919 [not cached]): MYOZ2 sequencing in 438 European familial-HCM patients found only two non-synonymous polymorphisms and no disease-causing mutations. The authors concluded MYOZ2 mutations are a rare cause of familial HCM. - Walsh et al. 2017 (Genet Med, PMID:27532257 [not cached]) compared 7,855 cardiomyopathy cases with 60,706 ExAC reference samples. Rare variants in many previously reported "minor" HCM genes showed no case excess. Use this as background for the ClinGen downgrade; check the supplement before claiming a MYOZ2-specific result. - Guo et al. 2017 (PMID:28296734): a five-generation Chinese family carried both MYH7-A719H and MYOZ2-L169G. Quote: "The sarcomere gene mutations MYH7-A719H and MYOZ2-L169G were detected in the HCM individuals in this pedigree." ClinGen excluded L169G as causative because of the co-occurring MYH7 variant. The paper's own framing is that "Multiple gene mutations may contribute to genetic anticipation in HCM." - Cecconi et al. 2016 (PMID:27600940): a targeted 19-gene NGS panel in Italian HCM patients reported a MYOZ2 variant among non-thick/thin-myofilament genes. Quote: "mutations in genes encoding only the non-TTm proteins are identifiable in patients with a milder HCM status." - Tran et al. 2024 (PMID:39682617): exome sequencing of Vietnamese cardiomyopathy patients reported a MYOZ2 variant of uncertain significance. The cohort was mainly dilated cardiomyopathy (DCM). Quote: "four were variants of uncertain significance in the ACTA2, ANK2, MYOZ2, and PRKAG2 genes." This is weak evidence and is not about HCM.

ClinGen (cached record CGGV:assertion_d74395ba-…-2022-10-27T160000.000Z): "MYOZ2 | HGNC:1330 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed". Curation summary: "The MYOZ2 gene has been related with HCM in 7 probands across 4 publications… The mechanism for disease is unknown." In KB terms this is gene_disease_validity: DISPUTED, classified_by: CLINGEN. PanelApp (Genomics England HCM panel) lists MYOZ2 as Red, low evidence.

Risk factors. None are specific to MYOZ2. General HCM modifiers apply, with low certainty: hypertension, obesity, and co-occurring sarcomere variants (digenic or compound states, as in Guo 2017).

Protective factors and gene–environment interactions. None documented in humans. The mouse data below show that MYOZ2 loss sensitizes the heart specifically to pressure overload, which suggests an interaction with afterload in principle. This has not been shown in patients.

3. Phenotypes

Patient-level data are limited to the Osio family and a few probands. Frequencies are therefore not available. HP IDs below are suggestions to verify with runoak; they are not checked bindings.

Phenotype Suggested HPO (verify) Notes
Left ventricular hypertrophy / asymmetric septal hypertrophy HP:0001712 LVH; HP:0001670 asymmetric septal hypertrophy defining feature
Hypertrophic cardiomyopathy HP:0001639 disease-level
LV outflow tract obstruction HP:0031645 (verify) not reported specifically for MYOZ2
Diastolic dysfunction HP:0025168 (verify)
Myocardial interstitial fibrosis HP:0031319? (verify) seen in mice (Ruggiero 2013)
Arrhythmia / atrial fibrillation HP:0011675 / HP:0005110 general HCM
Sudden cardiac death HP:0001645 reported in the Guo family, but confounded by MYH7
Dyspnea, chest pain, syncope, palpitations HP:0002094, HP:0100749, HP:0001279, HP:0001962 general HCM symptoms
  • Onset: adolescence to adulthood; age-dependent, as in HCM generally.
  • Severity: the Cecconi data suggest milder disease for non-myofilament genes.
  • Quality of life: no MYOZ2-specific data. HCM in general reduces exercise capacity, and quality of life is measured with the KCCQ in trials.

4. Genetic and molecular information

  • Gene: MYOZ2 (myozenin-2 / calsarcin-1 / FATZ-related protein 2), 264 aa. It belongs to the calsarcin family together with MYOZ1 (calsarcin-2) and MYOZ3. In adults it is expressed in heart and slow-twitch muscle. Frey 2000 (PMID:11114196): "calsarcin-1 is expressed specifically in adult cardiac and slow-twitch skeletal muscle." The same paper describes the binding role: calsarcins "tether calcineurin to alpha-actinin at the z-line of the sarcomere."
  • Variants:
  • S48P — segregating in the linkage family
  • I246M — single proband
  • L169G — co-occurs with MYH7, excluded by ClinGen
  • further missense variants from panel studies, with no functional support
  • Variant class and origin: germline heterozygous missense. No LoF, CNV or structural variants have been reported as causal. ClinVar entries are predominantly VUS or conflicting (check ClinVar live).
  • Mechanism of variant action: unknown. ClinGen states it explicitly. The mouse data suggest a dominant structural (Z-disc) effect rather than simple haploinsufficiency (see §6). Note that Myoz2⁻/⁻ mice do not develop spontaneous hypertrophy.
  • Modifiers, epigenetics, chromosomal abnormalities: none reported.

5. Environmental information

No toxins, infections or lifestyle factors are specific to CMH16. In general HCM, strenuous exertion is a historical trigger for sudden cardiac death; current guidelines permit individualised exercise. Pressure overload is the experimentally relevant stressor in mice (§6).

6. Mechanism and pathophysiology

Ordered causal chain. The provisional parts are labelled. 1. A heterozygous MYOZ2 missense variant (S48P, I246M) produces a mutant myozenin-2 that still incorporates into the Z-disc, co-localising with α-actinin. Mouse data. 2. The mutant protein leads to Z-disc disruption and misalignment. Shown by electron microscopy in transgenic mice. 3. Z-disc mechanosensing and signalling are altered, which results in changes in ERK1/2 and JNK MAPK phosphorylation. Mouse data; that this step causes hypertrophy is inferred. - Branch, not supported for mutants: loss of calcineurin inhibition → NFAT activation. Shown for knockout mice, but calcineurin activity was unchanged in mutant-transgenic mice. 4. Activation of the hypertrophic gene programme (ANF, BNP) leads to cardiomyocyte hypertrophy. 5. Cardiomyocyte hypertrophy plus interstitial fibrosis result in LVH with preserved systolic function, and then the clinical HCM phenotype. Diastolic dysfunction and arrhythmia are inferred from HCM in general.

Key evidence. - Ruggiero et al. 2013 (PMID:22987565, cached, full text): the authors generated transgenic mice expressing MYOZ2 S48P or I246M on a hemizygous endogenous background (Myoz2+/−). - "Mutant MYOZ2 mice showed molecular, cellular, and gross cardiac hypertrophy, preserved systolic function, and interstitial fibrosis." - "Electron microscopy showed disrupted and mal-aligned Z disks in the mutant mice." - Calcineurin activity "was unchanged in the mutant transgenic mice. However, levels of phospho-ERK1/2 and JNK54/46 were altered." - Conclusion: "the cardiac phenotype in HCM caused by MYOZ2 mutations might be independent of calcineurin activity… Z disk abnormalities might provide the stimulus for the induction of cardiac hypertrophy." - Frey et al. 2004 (PMID:15543153, cached): in Myoz2 knockout mice, "calsarcin-1 negatively modulates the functions of calcineurin." Loss "activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload." - Frank et al. 2007 (PMID:18025526, cached): with overexpression, "CS1 prevents Ang-II-induced cardiomyocyte hypertrophy at least in part via inhibition of calcineurin signaling."

Interpretation. Loss-of-function biology (knockout → calcineurin disinhibition) and the disease-variant biology (Z-disc disruption, calcineurin-independent) disagree. This is a good place for a KNOWLEDGE_GAP or HUMAN_MODEL_MISMATCH discussion. Human tissue, iPSC-cardiomyocyte, transcriptomic and proteomic data specific to MYOZ2 variants do not appear to exist; I found no GEO or PRIDE datasets.

Suggested ontology terms (verify every one): - GO biological processes: calcineurin-NFAT signaling cascade (GO:0033173); negative regulation of calcineurin-NFAT signaling (GO:0070884); cardiac muscle hypertrophy (GO:0003300); ERK1 and ERK2 cascade (GO:0070371); JNK cascade (GO:0007254); Z disc (CC, GO:0030018). - CL cell types: cardiac muscle cell (CL:0000746); fibroblast of cardiac tissue (CL:0002548).

7. Anatomical structures

  • Organ: heart. Left ventricle (UBERON:0002084) and interventricular septum (UBERON:0002094); verify both IDs.
  • Secondary involvement: left atrium, through AF and dilation.
  • Tissue: myocardium (UBERON:0002349).
  • Subcellular: sarcomeric Z-disc.
  • Skeletal muscle: slow-twitch fibres express MYOZ2, and knockout mice have excess slow fibres. No skeletal myopathy has been reported in patients.
  • Lateralization: asymmetric LV and septal hypertrophy.

8. Temporal development

Onset in adolescence or adulthood, insidious and age-dependent. Disease is slowly progressive or stable, with stages from preclinical genotype-positive through to the uncommon end-stage burnt-out form. The Guo family showed anticipation (median onset 63.5 → 38.5 → 18 years over three generations), but this is confounded by the MYH7 variant and accumulating variants. It should not be attributed to MYOZ2.

9. Inheritance and population

  • Inheritance: autosomal dominant (HP:0000006). Penetrance is incomplete and age-dependent, as inferred for HCM generally; no MYOZ2-specific estimate exists. Expressivity is variable.
  • Prevalence: HCM overall is about 1 in 500 (Maron 1995 CARDIA, PMID:7618393 [not cached]). The MYOZ2 share is too small to estimate: 1 of 516 probands in Osio, 0 of 438 in Posch.
  • Prevalence class: ultra-rare, effectively cases in the literature (fewer than 10 probands).
  • Founder effects, sex ratio: none known.

10. Diagnostics

  • Imaging: echocardiography or cardiac MRI showing wall thickness ≥15 mm, or ≥13 mm in relatives. Late gadolinium enhancement shows fibrosis.
  • Other tests: ECG, Holter, exercise testing, NT-proBNP.
  • Genetic testing: a multigene HCM panel or exome. MYOZ2 is not in the ClinGen-curated core HCM genes; with a Disputed classification, a MYOZ2 variant generally should not be used for cascade testing (2023 ESC and 2024 AHA/ACC guidance on genes with limited evidence).
  • Differential diagnosis:
  • other sarcomeric HCM (MYH7, MYBPC3)
  • Fabry disease (GLA)
  • PRKAG2 disease
  • Danon disease (LAMP2)
  • TTR amyloid
  • RASopathies
  • athlete's heart
  • hypertensive heart disease

11. Outcome and prognosis

No MYOZ2-specific data exist. For HCM generally, annual mortality is under 1% with contemporary care. The main complications are AF, heart failure, stroke and sudden cardiac death. SCD risk is assessed with the HCM Risk-SCD calculator or the AHA risk factors.

12. Treatment

All of this is generic HCM management, from the 2024 AHA/ACC guideline (PMID:38718139) and the 2023 ESC cardiomyopathy guideline (PMID:37622657); both [not cached].

  • Pharmacotherapy (NCIT:C15986 Pharmacotherapy):
  • beta-blockers and non-dihydropyridine calcium-channel blockers
  • disopyramide
  • cardiac myosin inhibitors: mavacamten (EXPLORER-HCM, PMID:32871100) and aficamten (SEQUOIA-HCM, PMID:38739079), both [not cached]
  • anticoagulation for AF
  • Procedures:
  • septal myectomy (NCIT:C15329 Surgical Procedure; carry the detail in preferred_term)
  • alcohol septal ablation
  • ICD implantation for SCD prevention (device-qualifier pattern)
  • transplantation (NCIT:C15289 Organ Transplantation) for end-stage disease
  • Genetic counseling (NCIT:C15240).
  • No gene-specific or advanced therapy: none exists for MYOZ2. Calcineurin modulation was proposed from mouse work (Frank 2007), but it is experimental only and has no trials.

13. Prevention

  • Primary prevention: none.
  • Secondary prevention: clinical screening of first-degree relatives with ECG and echo, regardless of genotype. Because MYOZ2 is Disputed, use clinical surveillance rather than predictive genotyping.
  • Tertiary prevention: SCD risk stratification and ICD; AF anticoagulation.

14. Other species

  • Natural disease: feline HCM is common, but it is linked to MYBPC3 (Maine Coon, Ragdoll) and not to MYOZ2. No natural MYOZ2 disease is known in animals (check OMIA).
  • Orthologs: Myoz2 in mouse; ZFIN has a myoz2 record (ZDB-GENE-040426-1853).

15. Model organisms

Model Phenotype Fidelity
Myoz2⁻/⁻ mouse (Frey 2004) calcineurin hyperactivity, excess slow fibres, fetal gene programme without hypertrophy; exaggerated hypertrophy after pressure overload (TAC) partial: models loss of function, not the disease variants
Transgenic MYOZ2 S48P / I246M on Myoz2+/− (Ruggiero 2013; MGI alleles MGI:5581488 and MGI:5581489) LVH, interstitial fibrosis, preserved EF, Z-disc disruption, altered ERK/JNK, calcineurin unchanged moderate; caveat that transgene levels were 15–48% of total MYOZ2
Calsarcin-1 transgenic overexpression (Frank 2007) protected against angiotensin-II-induced hypertrophy mechanistic only
Neonatal rat cardiomyocytes, adenoviral or lentiviral expression anti-hypertrophic effect of WT CS1; I246M did not change RCAN1.4 in vitro

No iPSC-cardiomyocyte or zebrafish models for MYOZ2 variants were found.

Recommendations for the dismech entry

  • Record the ClinGen tier verbatim in gene_disease_validity (DISPUTED, CLINGEN, cached CGGV id). relationship_type: CAUSATIVE would trigger the overstated audit class; consider a weaker type or a note.
  • Fetch before citing: run just fetch-reference for PMID:17347475, 18591919, 27532257 and the guideline and trial PMIDs before quoting them. The abstracts were not retrievable verbatim in this session.
  • Model the calcineurin discordance as a HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP discussion.
  • Re-check every HPO, GO, CL, UBERON and NCIT CURIE above. Several were written from memory and are flagged as such.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 15
Resolved 15
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 15
On topic 9
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:7618393 (1 mention) - Importance of an early tissue transfer in the treatment of complicated injuries of lower extremities.
  • shared terms: none

Weighed against this report's own most characteristic terms: myoz2, hcm, gene, disease, variant, clingen, cached, cardiac, hypertrophy, calcineurin, mice, family, mouse, cardiomyopathy, hypertrophic, found, z-disc, cmh16, i246m, proband.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 35
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 10
Terms named correctly 4
Terms named as a different term 3
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0013455 (1 mention) - the report calls it "MONDO"; MONDO calls it hypertrophic cardiomyopathy 16
  • HP:0031645 (1 mention) - the report calls it "verify"; HP calls it Saccular abdominal aortic aneurysm
  • HP:0025168 (1 mention) - the report calls it "verify"; HP calls it Left ventricular diastolic dysfunction

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0033173 (1 mention) - the report calls it "GO biological processes: calcineurin-NFAT signaling cascade"; GO calls it calcineurin-NFAT signaling cascade**
  • CL:0000746 (1 mention) - the report calls it "CL cell types: cardiac muscle cell"; CL calls it cardiac muscle cell**
  • UBERON:0002349 (1 mention) - the report calls it "Tissue: myocardium"; UBERON calls it myocardium**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.